The long-term objective of this research is to characterize the neurochemical alterations brought about by psychostimulant abuse in humans. Very little research has been carried out directly on human brains which might address the specific neurobiological consequences of amphetamine or cocaine abuse. To this end, molecular and histochemical analysis of postmortem brain tissue of human subjects who have an established premorbid history amphetamine or cocaine addiction will be compared to that of control subjects with no history od drug abuse. Alterations in specific neuronal populations, at the level of transcription and translation of relevant neurotransmitters enzymes, transport carriers, and neuropeptides, will be identified, localized and quantified. The relative amounts of mRNA expression in particular brain regions will be assessed with in situ hybridization histochemistry, while protein levels will be measured with the use of radioimmunoassay, and in vitro autoradiography will be used to localize and quantify receptor binding sites. An abundance of animal research has indicated that altered dopaminergic transmission within mesolimbic brain areas is a crucial neurochemical substrate for reward, whereas altered transmission in mesostrital brain areas is identified with stimulant-induced stereotyped behavior. In order to identify stable molecular changes associated with these phenomena, alterations in mRNA expression of neurochemical markers associated with dopamine neurons (i.e. dopamine receptors, dopamine transport carriers, and synthesizing enzymes) will be examined in limbic and extrapyramidal systems of the human brains. Analysis of the post- synaptic striatal neuropeptidergic systems that are linked to dopamine function will also be evaluated because selective alterations in the mRNA expression of dynorphin and enkephalin have previously been identified in human cocaine addicts. The localization of these pre-and post-synaptic changes will be compared with aspects of established anatomical connectivity and histochemical organization of the striatum so that molecular alterations in the matrix vs. patch compartments and limbic vs. sensorimotor regions can be differentially characterized. This work offers a unique opportunity to understand molecular processes of neurobiological dysfunction with a potentially enormous impact on expanding knowledge of human brain function in both the normal and drug- addicted condition. The social implications of this work are far reaching because drug abuse is on the increase worldwide. The research will provide understanding of basic molecular mechanisms in drug abuse with significant possibilities for developing targeted clinical treatments.